NFEPP explained

NFEPP (N-(3-fluoro-1-phenethylpiperidin-4-yl)-N-phenylpropionamide) is an analgesic opioid chemical, similar in structure to fentanyl, designed in 2016 by Spahn et al. from Free University of Berlin^[1] to avoid the standard negative side effects of opiates, including opioid overdose, by only targeting inflamed tissue.^{[2] [3]}

Inflamed tissue

Inflamed tissue has a lower pH value (~5–7) than non-inflamed tissue (7.4).^[4] Through computer simulation, scientists found a way to make the fentanyl analog only affect inflamed tissue via the addition of fluorine to the chemical structure. In experiment, it was shown that NFEPP produced injury-restricted analgesia in rats with different types of inflammatory pain without exhibiting typical opiate effects, including respiratory depression, sedation, constipation, and chemical seeking behavior.^{[5] [6] [7]}

As a result, NFEPP has the potential to reduce opioid addiction and dependency, as there is no effect on users who are not actually suffering from pain, as the chemical does not interact with non-inflamed brain tissue until much higher doses are reached.^[8]

Notes and References

1. Spahn V, Del Vecchio G, Labuz D, Rodriguez-Gaztelumendi A, Massaly N, Temp J, Durmaz V, Sabri P, Reidelbach M, Machelska H, Weber M, Stein C . A nontoxic pain killer designed by modeling of pathological receptor conformations . Science . 355 . 6328 . 966–969 . March 2017 . 28254944 . 10.1126/science.aai8636 . 2017Sci...355..966S . 206653322 .
2. Halford B . An opioid minus major side effects . Chemical & Engineering News . 95 . 10 . 8 . 2017.
3. Edwards SR, Blough BE, Cowart K, Howell GH, Araujo AA, Haskell JP, Huskinson SL, Rowlett JK, Brackeen MF, Freeman KB . Assessment of the Antinociceptive, Respiratory-Depressant, and Reinforcing Effects of the Low pKa Fluorinated Fentanyl Analogs, FF3 and NFEPP . Neuropharmacology . 110002 . May 2024 . 38754577 . 10.1016/j.neuropharm.2024.110002 .
4. Web site: Beth . Mole . Early study suggests new opioid is non-addictive, works only where it hurt . Ars Technica . March 4, 2017.
5. Rodriguez-Gaztelumendi A, Spahn V, Labuz D, Machelska H, Stein C . Analgesic effects of a novel pH-dependent μ-opioid receptor agonist in models of neuropathic and abdominal pain . Pain . 159 . 11 . 2277–2284 . November 2018 . 29994988 . 10.1097/j.pain.0000000000001328 . 6203420 .
6. Massaly N, Temp J, Machelska H, Stein C . Uncovering the analgesic effects of a pH-dependent mu-opioid receptor agonist using a model of nonevoked ongoing pain . Pain . 161 . 12 . 2798–2804 . December 2020 . 32639370 . 10.1097/j.pain.0000000000001968 . 220410251 .
7. Degro CE, Jiménez-Vargas NN, Tsang Q, Yu Y, Guzman-Rodriguez M, Alizadeh E, Hurlbut D, Reed DE, Lomax AE, Stein C, Bunnett NW, Vanner SJ . Evolving acidic microenvironments during colitis provide selective analgesic targets for a pH-sensitive opioid . Pain . 164. 11. June 2023 . 2501–2515 . 37326658 . 10.1097/j.pain.0000000000002956 . 10731875 . November 1, 2024 .
8. Baamonde A, Menéndez L, González-Rodríguez S, Lastra A, Seitz V, Stein C, Machelska H . A low pKa ligand inhibits cancer-associated pain in mice by activating peripheral mu-opioid receptors . Scientific Reports . 10 . 1 . 18599 . October 2020 . 33122720 . 10.1038/s41598-020-75509-4 . 7596718 . 2020NatSR..1018599B . free .